HPV has more than 100 genotypes. Among genotypes infecting mucosal epithelium (mucosal HPV), at least 15 types (high-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 73) are responsible for uterine cervical cancer.
HPV particles have an icosahedral capsid structure which is composed of 72 pentamers (capsomeres) of L1 protein and 12 molecules of L2 protein and within which DNA genomes are encapsulated. Upon overexpression of L1 protein alone by recombinant DNA technology, a capsid-like structure (L1-capsid) is formed. Upon co-expression with L2 protein, a capsid of the same composition as that of the virus particles is formed (L1/L2-capsid). The L1-capsid has strong immunogenicity and is shown to induce both antibody production and cellular immunity without any adjuvant when inoculated into animals. This immunogenicity is specific to the type of HPV, and immunization with type 16 L1-capsid induces reactions specific to type 16.
When used as a vaccine antigen, the L1-capsid can prevent HPV infection. Vaccines comprising the L1-capsids of HPV types 6, 11, 16 and 18 or HPV types 16 and 18 as antigens have already been developed abroad and are also marketed in Japan. However, these first-generation vaccine antigens are very highly type-specific and, for example, type 16 L1-capsid vaccines prevent only HPV type 16 infection. Thus, there is a demand for the development of a vaccine antigen which induces neutralizing antibodies common to the high-risk types.
The inventors of the present invention have previously found that the L2 protein of HPV type 16 contains type-common neutralization epitopes, and have shown that these epitopes can be used as a next-generation type-common HPV vaccine antigen (Non-patent Document 1, Non-patent Document 2, Non-patent Document 3, and Non-patent Document 4).
Above all, the amino acid sequence of amino acids 56-75 in the HPV16 L2 protein is highly conserved among all high-risk types of HPV, and this region can induce cross-neutralizing antibodies effective against a wide range of types when inoculated into animals in the form of a conjugate with keyhole limpet hemocyanin (KLH) (KLH-P56/75) or in the form of a chimeric capsid composed of a chimeric protein carrying this region inserted into amino acids 430-433 in type 16 L1 protein (16L1-430(56/75) chimeric capsid) (Patent Document 1, Non-patent Document 3, and Non-patent Document 4). As indicated by these findings, antigens having the amino acid sequence of amino acids 56-75 in the L2 protein are promising candidates for use as next-generation HPV vaccines effective against all high-risk types of HPV and are now under development for practical use.